15.10.2007

Characteristics of urban regions and all-cause mortality in working-age population: Effects of social environment and interactions with individual unemployment

Blomgren, J. and Valkonen, T.

Demographic Research. 2007; 17: 109-134. Journal Article.

Using Finnish register data on individuals linked to information on urban regions, this study aimed to estimate the effects of some regional characteristics on all-cause mortality among working-age population in 1995-2001, and to find out whether these effects are different among those long-term unemployed than among others. Multilevel Poisson regression models were used. The characteristics of regions included unemployment rate, level of urbanisation, voting turnout, a summary measure of family cohesion, and the geographic location of the region. Our study showed that effects of most area characteristics on mortality were clear among those who suffered from long-term unemployment in the baseline but not among others, adjusting for basic socio-demographic characteristics of the individuals. The results thus suggest that the weaker in the society are more vulnerable to the effects of social environment than those better off.

The association between life events and suicide intent in self-poisoners with and without a history of deliberate self-harm: A preliminary study

Crane, C., Williams, J. M. G., Hawton, K., Arensman, E., Hjelmeland, H., Polit, Bille-Brahe, U., Corcoran, P., De Leo, D., Fekete, S., Grad, O., Haring, C., Kerkhof, A., Lonnqvist, J., Michel, K., Renberg, E. S., Schmidtke, A., Van Heeringen, C. and Wasserman, D.

Suicide and Life-Threatening Behavior. 2007; 37(4): 367-378. Journal Article. IF 1.624

The associations between life events in the 12 months preceding an episode of self-poisoning resulting in hospital attendance (the index episode), and the suicide intent of this episode were compared in individuals for whom the index episode was their first, episode and in individuals in whom it was a recurrence of DSH. Results indicated a significant interaction between independent life events, repetition status, and gender in the prediction of suicide intent, the association between life events and intent being moderated by repetition status in women only. The results provide preliminary evidence to suggest the presence of a suicidal process in women, in which the impact of negative life events on suicide intent diminishes across episodes.

On-treatment Diastolic blood pressure and prognosis in systolic hypertension

Fagard, R. H., Staessen, J. A., Thijs, L., Celis, H., Bulpitt, C. J., de Leeuw, P. W., Leonetti, G., Tuomilehto, J. and Yodfat, Y.

Archives of Internal Medicine. 2007; 167(17): 1884-1891. Journal Article. IF 7.920

Background: It has been suggested that low diastolic blood pressure (BP) while receiving antihypertensive treatment (hereinafter called on-treatment BP) is harmful in older patients with systolic hypertension. We examined the association between on-treatment diastolic BP, mortality, and cardiovascular events in the prospective placebo-controlled Systolic Hypertension in Europe Trial.

Methods: Elderly patients with systolic hypertension were randomized into the double-blind first phase of the trial, after which all patients received active study drugs (phase 2). We assessed the relationship between outcome and on-treatment diastolic BP by use of multivariate Cox regression analysis during receipt of placebo (phase 1) and during active treatment (phases 1 and 2).

Results: Rates of noncardiovascular mortality, cardiovascular mortality, and cardiovascular events were 11.1, 12.0, and 29.4, respectively, per 1000 patient-years with active treatment (n = 2358) and 11.9, 12.6, and 39.0, respectively, with placebo (n = 2225). Noncardiovascular mortality, but not cardiovascular mortality, increased with low diastolic BP with active treatment(P < . 005) and with placebo (P < . 05); for example, hazard ratios for lower diastolic BP, that is, 65 to 60 mm Hg, were, respectively, 1.15 (95% confidence interval, 1.00-1.31) and 1.28 (95% confidence interval, 1.03-1.59). Low diastolic BP with active treatment was associated with increased risk of cardiovascular events, but only in patients with coronary heart disease at baseline (P < . 02; hazard ratio for BP 65-60 mm Hg, 1.17; 95% confidence interval, 0.98-1.38).

Conclusions: These findings support the hypothesis that antihypertensive treatment can be intensified to prevent cardiovascular events when systolic BP is not under control in older patients with systolic hypertension, at least until diastolic BP reaches 55 mm Hg. However, a prudent approach is warranted in patients with concomitant coronary heart disease, in whom diastolic BP should probably not be lowered to less than 70 mm Hg.

Incidence of schizophrenia in a nationwide cohort of patients with type 1 diabetes mellitus

Juvonen, H., Reunanen, A., Haukka, J., Muhonen, M., Suvisaari, J., Arajarvi, R., Partonen, T. and Lonnqvist, J.

Archives of General Psychiatry. 2007; 64(8): 894-899. Journal Article. IF 13.936

Context: Patients with schizophrenia have an increased risk of type 2 diabetes mellitus. However, very few studies have dealt with the association of type 1 diabetes and schizophrenia. Preliminary evidence points to a possible inverse association.

Objective: To investigate the incidence of schizophrenia in a nationwide cohort of patients with type 1 dia betes born in 1950 through 1959 in Finland.

Design: A cohort study of individuals born in 1950 through 1959 with a follow-up of 1969 through 1991.

Setting: Finland. Patients: All individuals born in 1950 through 1959 with type I diabetes were identified through nationwide registers. The incidence of schizophrenia until 1992 among the total 1950-1959 cohort and in individuals with type I diabetes was calculated using information from 3 health care registers.

Main Outcome Measure: incidence of schizophrenia.

Results: The incidence of schizophrenia was 0.21 per 10 000 person-years in the group with type I diabetes and 0.56 per 10 000 person-years in the group without type I diabetes (P<.001).

Conclusion: The incidence of schizophrenia is decreased in patients with type I diabetes.

Dysfunction in early auditory processing in major depressive disorder revealed by combined MEG and EEG

Kahkonen, S., Yamashita, H., Rytsala, H., Suominen, K., Ahveninen, J. and Isometsa, E.

Journal of Psychiatry & Neuroscience. 2007; 32(5): 316-322. Journal Article. IF 4.100

Background: Patients with major depressive disorder (MDD) show impairments in cognitive functions. However, neural mechanisms underlying these disturbances are poorly understood. We investigated whether MDD affects neural mechanisms of involuntary attention studied by auditory evoked potentials (AEPs) and auditory evoked magnetic fields (AEFs).

Methods: AEPs and AEFs were studied in a passive odd-ball paradigm in 13 drug-free patients with unipolar MDD during an acute episode and 12 age-and sex-matched healthy subjects. Auditory responses to monaurally presented frequent " standard" tones, infrequent " deviant" tones (10% and 20% frequency change) and occasional " novel" sounds (complex sounds) were simultaneously recorded with whole-head magnetoencephalography (MEG) and electroencephalography (EEG).

Results: P1 and P1 m latencies were decreased in patients with MDD, compared with those in healthy subjects. Further, the mismatch negativity amplitude to the 10% frequency deviance in the EEG, but not in the MEG, was increased in MDD. We observed no differences in N1/N1 m and P3a responses in the MEG and EEG. The magnitude of decrease in P1/P1 m latency correlated negatively with the severity of depression in the patients.

Conclusions: Early auditory processing is impaired in patients with MDD during an acute episode, probably reflecting dysfunctional frontotemporal neural circuits. These dysfunctions may contribute to the cognitive disturbances observed in people with MDD.

Epidemiology and course of anorexia nervosa in the community

Keski-Rahkonen, A., Hoek, H. W., Susser, E. S., Linna, M. S., Sihvola, E., Raevuori, A., Bulik, C. M., Kaprio, J. and Rissanen, A.

American Journal of Psychiatry. 2007; 164(8): 1259-1265. Journal Article. IF 8.250

Objective: Most previous studies of the prevalence, incidence, and outcome of anorexia nervosa have been limited to cases detected through the health care system, which may bias our understanding of the disorder's incidence and natural course. The authors sought to describe the onset and outcomes of anorexia nervosa in the general population.

Method: Lifetime prevalences, incidence rates, and 5-year recovery rates of anorexia nervosa were calculated on the basis of data from 2,881 women from the 1975-1979 birth cohorts of Finnish twins. Women who screened positive for eating disorder symptoms (N=292), their screennegative female co-twins (N=134), and 210 randomly selected screen-negative women were assessed for lifetime eating disorders by telephone by experienced clinicians. To assess outcomes after clinical recovery and to detect residua of illness, women who had recovered were compared with their unaffected co-twins and healthy unrelated women on multiple outcome measures.

Results: The lifetime prevalence of DSM-IV anorexia nervosa was 2.2%, and half of the cases hail not been detected in the health care system. The incidence of anorexia nervosa in women between 15 and 19 years of age was 270 per 100,000 person-years. The 5-year clinical recovery rate was 66.8%. Outcomes did not differ between detected and undetected cases. After clinical recovery, the residua of illness steadily receded. By 5 years after clinical recovery, most probands had reached complete or nearly complete psychological recovery and closely resembled their unaffected co-twins and healthy women in weight and most psychological and social measures.

Conclusions: The authors found a substantially higher lifetime prevalence and incidence of anorexia nervosa than reported in previous studies, most of which were based on treated cases. Most women recovered clinically within 5 years, and thereafter usually progressed toward full recovery.

A 15-year national follow-up: legislation is not enough to reduce the use of seclusion and restraint

Keski-Valkama, A., Sailas, E., Eronen, M., Koivisto, A. M., Lonnqvist, J. and Kaltiala-Heino, R.

Social Psychiatry and Psychiatric Epidemiology. 2007; 42(9): 747-752. Journal Article. IF 1.577

Background Seclusion and restraint are frequent but controversial coercive measures used in psychiatric treatment. Legislative efforts have started to emerge to control the use of these measures in many countries. In the present study, the nationwide trends in the use of seclusion and restraint were investigated in Finland over a 15-year span which was characterised by legislative changes aiming to clarify and restrict the use of these measures.

Method The data were collected during a predetermined week in 1990, 1991, 1994, 1998 and 2004, using a structured postal survey of Finnish psychiatric hospitals. The numbers of inpatients during the study weeks were obtained from the National Hospital Discharge Register.

Results The total number of the secluded and restrained patients declined as did the number of all inpatients during the study weeks, but the risk of being secluded or restrained remained the same over time when compared to the first study year. The duration of the restraint incidents did not change, but the duration of seclusion increased. A regional variation was found in the use of coercive measures.

Conclusion Legislative changes solely cannot reduce the use of seclusion and restraint or change the prevailing treatment cultures connected with these measures. The use of seclusion and restraint should be vigilantly monitored and ethical questions should be under continuous scrutiny.

HIV outbreak among injecting drug users in the Helsinki region: social and geographical pockets

Kivela, P., Krol, A., Simola, S., Vaattovaara, M., Tuomola, P., Brummer-Korvenkontio, H. and Ristola, M.

European Journal of Public Health. 2007; 17(4): 381-386. Journal Article. IF 1.481

Background: Incidence of newly diagnosed HIV infections among injecting drug users (IDUs) in Helsinki rose from 0 per 100000 inhabitants in 1997 to 2.9 in 1998 and to 11.1 in 1999. Thereafter incidence declined to 2.1 in 2003.

Methods: Data were collected from interviews with HIV-positive IDUs who attended the University Hospital in Helsinki from 1998 until 2003. We studied the sociodemographic profile and spatial distribution of IDUs who were diagnosed in the beginning of the outbreak and those diagnosed later. The indicator for the spatial differentiation within the metropolitan area is employed males aged 25-64.

Results: The outbreak occurred among a marginalized population of IDUs characterized by along history of injecting drug use (10.7 years), mean age 32 years, homelessness (66.3%), history of imprisonment (74.7%) and psychiatric hospital care (40.6%). Compared with 98 early cases diagnosed during the first 2 years until 2000, 47 recent cases diagnosed after 2001 were 4 years older, and as marginalized. Except for the city centre, both early and recent cases had been living or using drugs in the same deprived neighbourhoods with the highest unemployment rates. Up to 40% of cases in the two big geographical clusters did not have contact with the city centre, where the needle exchange services were available.

Conclusions: The Finnish HIV outbreak is restricted socially to a very marginalized IDU population, and spatially to local pockets of poverty. In low prevalence countries, prevention programs should be targeted early at high-risk areas and populations.

Ranking cancer risks of organic hazardous air pollutants in the United States

Loh, M. M., Levy, J. I., Spengler, J. D., Houseman, E. A. and Bennett, D. H.

Environmental Health Perspectives. 2007; 115(8): 1160-1168. Journal Article. IF 5.861

BACKGROUND: In this study we compared cancer risks from organic hazardous air pollutants (HAPs) based on total personal exposure summed across different microenvironments and exposure pathways.

METHODS: We developed distributions of personal exposure concentrations using field monitoring and modeling data for inhalation and, where relevant, ingestion pathways. We calculated risks for a nonoccupationally exposed and nonsmoking population using U.S. Environmental Protection Agency (EPA) and California Office of Environmental Health and Hazard Assessment (OEHHA) unit risks. We determined the contribution to risk from indoor versus outdoor sources using indoor/outdoor ratios for gaseous compounds and the infiltration factor for particle-bound compounds.

RESULTS: With OEHHA's unit risks, the highest ranking compounds based on the population median are 1,3-butadiene, formaldehyde, benzene, and dioxin, with risks on the order of 10(-4)-10(-5). The highest risk compounds with the U.S. EPA unit risks were dioxin, benzene, formaldehyde, and chloroform, with risks on a similar order of magnitude. Although indoor exposures are responsible for nearly 70% of risk using OEHHA's unit risks, when infiltration is accounted for, inhalation of outdoor sources contributed 50% to total risk, on average. Additionally, 15% of risk resulted from exposures through food, mainly due to dioxin.

CONCLUSIONS: Most of the polycyclic aromatic hydrocarbon, benzene, acetaldehyde, and 1,3-butadiene risk came from outdoor sources, whereas indoor sources were primarily responsible for chloroform, formaldehyde, and naphthalene risks. The infiltration of outdoor pollution into buildings, emissions from indoor sources, and uptake through food are all important to consider in reducing overall personal risk to HAPs.

Surveillance of injury-related deaths: medicolegal autopsy rates and trends in Finland

Lunetta, P., Lounamaa, A. and Sihvonen, S.

Injury Prevention. 2007; 13(4): 282-284. Journal Article. IF 1.844

Medicolegal autopsies are a vital tool for obtaining reliable injury mortality data. In Finland, medicolegal autopsies have increased from 13.6% of all deaths in 1970 to 23.8% in 2004. In fact, medicolegal autopsies are performed in 87.2% of all unintentional injury deaths, 98.3% of homicides and 99.5% of suicides. Finland has exceedingly high medicolegal autopsy rates compared with other countries. Autopsy rates should be appropriately considered when performing international comparisons of injury-related deaths.

Sexual Behavior in young adulthood: A population-based twin study

Mustanski, B., Viken, R. J., Kaprio, J., Winter, T. and Rose, R. J.

Health Psychology. 2007; 26(5): 610-617. Journal Article. IF 3.693

Objective: With behavior genetic analyses of data from young adult twins, we evaluated theoretical perspectives that differentially emphasize biological dispositions, social/cultural factors, or universal pathways to explain individual differences in sexual behaviors.

Design: We fit biometric sex limitation models to three aspects of sexual behavior reported by 4,925 Finnish twins ages 23-27.

Main Outcome Measure: From a postal questionnaire, we obtained self-report information on initiation/abstinence of sexual intercourse, onset age, and number of sexual partners.

Results: Genetic and non-shared environmental influences were significant for all three measures. There were trends for common environmental influences on initiation and, in females, age at first intercourse. Some differential effects in males and females were found. Results comparing onset age and number of partners among experienced twins from pairs concordant and discordant for initiation found genetic and environmental influences on initiation/abstinence overlapped those found for the other aspects of sexual behavior.

Conclusions: These results document genetic variation in individual differences in sexual behavior of young adults. Incorporating genetic dispositions into integrated models of sexual behavior will facilitate more effective health promotion and risk taking intervention.

IFN regulatory factor family members differentially regulate the expression of type III IFN (IFN-lambda) genes

Osterlund, P. I., Pietilae, T. E., Veckman, V., Kotenko, S. V. and Julkunen, I.

Journal of Immunology. 2007; 179(6): 3434-3442. Journal Article. IF 6.293

Virus replication induces the expression of antiviral type I (IFN-alpha beta) and type III (IFN-lambda 1-3 or IL-28A/B and IL-29) IFN genes via TLR-dependent and -independent pathways. Although type III IFNs differ genetically from type I IFNs, their similar biological antiviral functions suggest that their expression is regulated in a similar fashion. Structural and functional characterization of the IFN-lambda I and IFN-lambda 3 gene promoters revealed them to be similar to IFN-beta and IFN-alpha genes, respectively. Both of these promoters had functional IFN-stimulated response element and NF-kappa B binding sites. The binding of IFN regulatory factors (IRF) to type III IFN promoter IFN-stimulated response element sites was the most important event regulating the expression of these genes. Ectopic expression of the components of TLR7 (MyD88 plus IRF1/IRF7), TLR3 (Toll/IL-IR domain-containing adapter-inducing factor), or retinoic acid-inducible gene I (RIG-I) signal transduction pathways induced the activation of IFN-lambda I promoter, whereas the IFN-lambda 3 promoter was efficiently activated only by overexpression of MyD88 and IRF7. The ectopic expression of Pin1, a recently identified suppressor for IRF3-dependent antiviral response, decreased the IFN promoter activation induced by any of these three signal transduction pathways, including the MyD88-dependent one. To conclude, the data suggest that the IFN-lambda 1 gene is regulated by virus-activated IRF3 and IRF7, thus resembling that of the IFN-beta gene, whereas IFN-beta gene expression is mainly controlled by IRF7, thus resembling those of IFN-alpha genes.

Adolescent adjustment disorder: Precipitant stressors and distress symptoms of 89 outpatients

Pelkonen, M., Marttunen, M., Henriksson, M. and Lonnqvist, J.

European Psychiatry. 2007; 22(5): 288-295. Journal Article. IF 1.463

Objective. - Research on adolescent adjustment disorder (AD) is scarce. We characterized adolescent outpatients with AD in psychosocial background and treatment received compared with patients with other non-psychotic disorders (OND). Furthermore, we explored precipitant stressors, distress symptoms and behavioral problems among males and females with AD.

Method. - Data were collected prospectively on 290 consecutive psychiatric outpatients, aged 12-22 yrs, at a secondary care clinic in Finland. DSM-III-R diagnoses were assigned, based on all available information, at the end of treatment.

Results. - AD was the second most common diagnosis among non-psychotic patients (31 % of 290). Compared to OND-patients, those with AD were predominantly female and had less severe psychosocial impairment. In multivariate comparisons school-related stressors, problems with law and restlessness characterized males, and parental illness and internalizing symptoms females with AD. Intensity and duration of treatment of AD-patients varied widely.

Conclusions. - Adjustment disorder comprised a common clinical entity among adolescent outpatients. Psychiatric assessment and treatment should be individually targeted by taking into account gender-specific stressors and distress symptoms among young people with AD.

(C) 2006 Elsevier Masson SAS. All rights reserved.

Variation of the transcription factor 7-like 2 (TCF7L2) gene predicts impaired fasting glucose in healthy young adults - The cardiovascular risk in Young Finns Study

Raitakari, O. T., Ronnemaa, T., Huupponen, R., Viikari, L., Fan, M., Marniemi, J., Hutri-Kahonen, N., Viikari, J. S. A. and Lehtimakimd, T.

Diabetes Care. 2007; 30(9): 2299-2301. Journal Article. IF 7.912

CanGEM: mining gene copy number changes in cancer

Scheinin, I., Myllykangas, S., Borze, I., Bohling, T., Knuutila, S. and Saharinen, J.

Nucleic Acids Res. 2007. Journal Article. IF

The use of genome-wide and high-throughput screening methods on large sample sizes is a well-grounded approach when studying a process as complex and heterogeneous as tumorigenesis. Gene copy number changes are one of the main mechanisms causing cancerous alterations in gene expression and can be detected using array comparative genomic hybridization (aCGH). Microarrays are well suited for the integrative systems biology approach, but none of the existing microarray databases is focusing on copy number changes. We present here CanGEM (Cancer GEnome Mine), which is a public, web-based database for storing quantitative microarray data and relevant metadata about the measurements and samples. CanGEM supports the MIAME standard and in addition, stores clinical information using standardized controlled vocabularies whenever possible. Microarray probes are re-annotated with their physical coordinates in the human genome and aCGH data is analyzed to yield gene-specific copy numbers. Users can build custom datasets by querying for specific clinical sample characteristics or copy number changes of individual genes. Aberration frequencies can be calculated for these datasets, and the data can be visualized on the human genome map with gene annotations. Furthermore, the original data files are available for more detailed analysis. The CanGEM database can be accessed at http://www.cangem.org/.

The mammalian oxysterol-binding protein-related proteins (ORPs) bind 25-hydroxycholesterol in an evolutionarily conserved pocket

Suchanek, M., Hynynen, R., Wohlfahrt, G., Lehto, M., Johansson, M., Saarinen, H., Radzikowska, A., Thiele, C. and Olkkonen, V. M.

Biochemical Journal. 2007; 405: 473-480. Journal Article. IF 4.100

OSBP (oxysterol-binding protein) homologues, ORPs (OSBP-related proteins), constitute a 12-member family in mammals. We employed an in vitro [H-3]25OH (25-hydroxycholesterol)-binding assay with purified recombinant proteins as well as live cell photo-cross-linking with [H-3]photo-25OH and [H-3]photoCH (photo-cholesterol), to investigate sterol binding by the mammalian ORPs. ORP1 and ORP2 [a short ORP consisting of an ORD (OSBP-related ligand-binding domain) only] were in vitro shown to bind 25OH. GST (glutathione S-transferase) fusions of the ORP1L [long variant with an N-terminal extension that carries ankyrin repeats and a PH domain (pleckstrin homology domain)] and ORP1S (short variant consisting of an ORD only) variants bound 25OH with similar affinity (ORP1L, K-d =9.7 x 10(-8)M; ORP1S, K-d = 8.4 x 10(-8) M), while the affinity of GST-ORP2 for 25OH was lower (Kd = 3.9 x 10(-6) M). Molecular modelling suggested that ORP2 has a sterol-binding pocket similar to that of Saccharomyces cerevisiae Osh4p. This was confirmed by site-directed mutagenesis of residues in proximity of the bound sterol in the structural model. Substitution of Ile(249) by tryptophan or LyS(150) by alanine markedly inhibited 25OH binding by ORP2. In agreement with the in vitro data, ORP1L, ORP1S, and ORP2 were cross-linked with photo-25OH in live COS7 cells. Furthermore, in experiments with either truncated cDNAs encoding the OSBP-related ligand-binding domains of the ORPs or the full-length proteins, photo-25OH was bound to OSBP, ORP3, ORP4, ORP5, ORP6, ORP7, ORP8, ORP10 and ORP11. In addition, the ORP1L variant and ORP3, ORP5, and ORP8 were cross-linked with photoCH. The present study identifies ORP1 and ORP2 as OSBPs and suggests that most of the mammalian ORPs are able to bind sterols.

Role of genetic and environmental influences on heart rate variability in middle-aged men

Uusitalo, A. L. T., Vanninen, E., Levalahti, E., Battie, M. C., Videman, T. and Kaprio, J.

American Journal of Physiology-Heart and Circulatory Physiology. 2007; 293(2): H1013-H1022. Journal Article. IF 3.724

Role of genetic and environmental influences on heart rate variability in middle-aged men. Am J Physiol Heart Circ Physiol 293: H1013 - H1022, 2007. First published March 30, 2007; doi:10.1152/ajpheart.00475.2006. - Our aim was to estimate causal relationships of genetic factors and different specific environmental factors in determination of the level of cardiac autonomic modulation, i.e.,heart rate variability (HRV), in healthy male twins and male twins with chronic diseases. The subjects were 208 monozygotic (MZ, 104 healthy) and 296 dizygotic (DZ, 173 healthy) male twins. A structured interview was used to obtain data on lifetime exposures of occupational loading, regularly performed leisure-time sport activities, coffee consumption, smoking history, and chronic diseases from 12 yr of age through the present. A 5-min ECG at supine rest was recorded for the HRV analyses. In univariate statistical analyses based on genetic models with additive genetic, dominance genetic, and unique environmental effects, genetic effects accounted for 31 - 57% of HRV variance. In multivariate statistical analysis, body mass index, percent body fat, coffee consumption, smoking, medication, and chronic diseases were associated with different HRV variables, accounting for 1 - 11% of their variance. Occupational physical loading and leisure-time sport activities did not account for variation in any HRV variable. However, in the subgroup analysis of healthy and diseased twins, occupational loading explained 4% of the variability in heart periods. Otherwise, the interaction between health status and genetic effects was significant for only two HRV variables. In conclusion, genetic factors accounted for a major portion of the interindividual differences in HRV, with no remarkable effect of health status. No single behavioral determinant appeared to have a major influence on HRV. The effects of medication and diseases may mask the minimal effect of occupational loading on HRV.